Alexander-Miller Laboratory

My laboratory is interested in the regulation of adaptive immunity. We have two major areas of focus- 1) development of vaccines for use in neonates and 2) regulation of CD4+ and CD8+ T cell responses during coinfection.

1) Adjuvants can enhance the vaccine mediated immune response in neonates. Influenza virus remains one of the leading causes of morbidity and mortality worldwide. Infants less than 6 months of age are particularly vulnerable to the development of severe disease following infection. Diseases associated with influenza virus infection in children include otitis media, pneumonia, myositis, and croup. While oseltamivir (Tamiflu), one of the two FDA-approved anti-influenza drugs, can be used in infants aged 2 weeks and older to treat influenza, concerns exist due to the potential for adverse effects, drug-resistance, and limited effectiveness in young infants.

Currently, there are two approved approaches for influenza vaccination in the United States- intramuscular administration of inactivated influenza virus and intranasal administration of live-attenuated influenza vaccine (LAIV). The former is approved only for individuals aged 6 months and older and the latter for healthy, non-pregnant individuals aged 2-49 years. Thus, neither is approved for use in the vulnerable neonate population. While the lack of approval of these vaccines in very young infants may reflect some safety concerns, a principal factor is the limited immune response that is generated in infants following vaccination. Thus, there is a critical need for new approaches that can elicit immunity in this population.

There is a significant body of literature demonstrating functional defects in the neonatal immune system. These defects span innate and adaptive immune responses. Our studies test the hypothesis that TLR agonists can promote stronger adaptive immune responses following influenza vaccination of neonates. To facilitate these studies we have established an infant nonhuman primate model. This was critical as the distribution and/or function of TLR in primates varies from mice. Another major advantage to this approach is the significantly longer period of infancy in NHP, which allows assessment of boosting strategies. Studies are underway to assess the ability of the experimental adjuvants to promote protective immune responses in the infants.

2) Modulation of the ongoing influenza-specific adaptive response following coinfection with Streptococcus pneumoniae. Influenza A virus (IAV) associated bacterial pneumonia is a significant cause of morbidity and mortality. During the 1918 “Spanish flu” pandemic, the vast majority of fatal cases were complicated by bacterial pneumonias, with Streptococcus pneumoniae (Spn) accounting for the preponderance of bacterial infections. Data from more recent pandemics in 1957, 1968, and 2009 reveal a similar phenomenon; for example, in 2009 as many as 56% of hospitalized patients tested positive for IAV associated bacterial pneumonias. Thus, coinfection with Spn and influenza virus poses a high public health concern.

Given the significant disease associated with influenza virus and pneumococcus infections, considerable effort has been directed towards understanding the mechanisms responsible for bacterial outgrowth under these circumstances. These studies have revealed influenza-mediated alterations in the innate immune system that promote bacterial survival and growth, including decreased phagocytosis and loss of alveolar macrophages. Interestingly, in addition to increased bacterial burden, there is evidence that viral load in the lung is augmented following bacterial coinfection, suggesting bacteria-mediated changes are present that promote virus infection and/or growth.

Surprisingly, our understanding of the regulation of the ongoing adaptive immune response to influenza virus following coinfection with Spn is lacking. We have made the critical observation that infection of mice with influenza virus followed by coinfection with a non-invasive strain of Streptococcus pneumoniae leads to a significant decrease in the virus-specific CD8+ T cell response in the lung. Our studies suggest this reduction in influenza-specific effector cells contributes to disease in coinfected animals. The reduced number of lung effector cells in coinfected animals is associated with increased death as well as a reduction in cytokine production in surviving cells. Negative regulation of cells in the mediastinal lymph node (MLN) is minimal compared to that present in the lung, supporting a model of negative regulation in the tissue harboring high pathogen burden. These results elucidate a new aspect of immune regulation as a result of entry of a coinfecting pathogen, modulation of ongoing adaptive immune responses in the lung. Current studies are focused on understanding the mechanistic basis for this negative regulation and how it might extend to other populations in the lung.

Disclaimer: The information on this website is for general informational purposes only and SHOULD NOT be relied upon as a substitute for sound professional medical advice, evaluation or care from your physician or other qualified health care provider.